Progress in the Consideration of Possible Sex Differences in Drug Interaction Studies

Author(s):Panjasaram Naidoo*,
Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu Natal, KwaZulu Natal, South AfricaManoranjenni Chetty.
Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu Natal, KwaZulu Natal, South Africa

Graphical Abstract:

Abstract:

Background: Anecdotal evidence suggests that there may be sex differences in Drug-drug Interactions
(DDI) involving specific drugs. Regulators have provided general guidance for the inclusion of females in clinical
studies. Some clinical studies have reported sex differences in the Pharmacokinetics (PK) of CYP3A4 substrates,
suggesting that DDI involving CYP3A4 substrates could potentially show sex differences.

Objective: The aim of this review was to investigate whether recent prospective DDI studies have included both
sexes and whether there was evidence for the presence or absence of sex differences with the DDIs.

Methods: The relevant details from 156 drug interaction studies within 124 papers were extracted and evaluated.

Results: Only eight studies (five papers) compared the outcome of the DDI between males and females. The majority
of the studies had only male volunteers. Five studies had females only while 60 had males only, with 7.7% of the
studies having an equal proportion of both sexes. Surprisingly, four studies did not specify the sex of the subjects.

Based on the limited number of studies comparing males and females, no specific trends or conclusions were evident.
Sex differences in the interaction were reported between ketoconazole and midazolam as well as clarithromycin and
midazolam. However, no sex difference was observed with the interaction between clarithromycin and triazolam or
erythromycin and triazolam. No sex-related PK differences were observed with the interaction between ketoconazole
and domperidone, although sex-related differences in QT prolongation were observed.

Conclusion: This review has shown that only limited progress had been made with the inclusion of both sexes in
DDI studies.

Federal Register Notice. The study and evaluation of gender differences in the clinical evaluation of drugs. Guideline for the study and evaluation of gender differences in the clinical evaluation of drugs. FR Notice, 1993, 58, 39406-39416.

Current Drug Metabolism

Title:Progress in the Consideration of Possible Sex Differences in Drug Interaction Studies

VOLUME: 20 ISSUE: 2

Author(s):Panjasaram Naidoo* and Manoranjenni Chetty

Affiliation:Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu Natal, KwaZulu Natal, Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu Natal, KwaZulu Natal

Background: Anecdotal evidence suggests that there may be sex differences in Drug-drug Interactions
(DDI) involving specific drugs. Regulators have provided general guidance for the inclusion of females in clinical
studies. Some clinical studies have reported sex differences in the Pharmacokinetics (PK) of CYP3A4 substrates,
suggesting that DDI involving CYP3A4 substrates could potentially show sex differences.

Objective: The aim of this review was to investigate whether recent prospective DDI studies have included both
sexes and whether there was evidence for the presence or absence of sex differences with the DDIs.

Methods: The relevant details from 156 drug interaction studies within 124 papers were extracted and evaluated.

Results: Only eight studies (five papers) compared the outcome of the DDI between males and females. The majority
of the studies had only male volunteers. Five studies had females only while 60 had males only, with 7.7% of the
studies having an equal proportion of both sexes. Surprisingly, four studies did not specify the sex of the subjects.

Based on the limited number of studies comparing males and females, no specific trends or conclusions were evident.
Sex differences in the interaction were reported between ketoconazole and midazolam as well as clarithromycin and
midazolam. However, no sex difference was observed with the interaction between clarithromycin and triazolam or
erythromycin and triazolam. No sex-related PK differences were observed with the interaction between ketoconazole
and domperidone, although sex-related differences in QT prolongation were observed.

Conclusion: This review has shown that only limited progress had been made with the inclusion of both sexes in
DDI studies.